Lipid-selective antioxidants and their preparation and use

ABSTRACT

Lipid-selective antioxidants of the formula I 
     
         (A).sub.a (L)(X).sub.a,                                    (I), 
    
     in which 
     A=an antioxidative component, 
     L=a bridging member, 
     X=a lipophilic component 
     a and a&#39;=independently of one another the numbers 1 or 2. 
     The compounds are used for the protection of lipid-containing substances against oxidation and in pharmaceuticals for the prophylaxis and treatment of diseases in which bioradicals are involved, in particular of coronary, circulatory and vascular diseases.

Antioxidants are used in the foodstuffs industry as preservativeadditives as foodstuffs can undergo undesired oxidative changes onstorage. It is also known that the lipid components of the foodstuffsare particularly sensitive to oxidation and become rancid on storage inair as peroxides and unsaturated aldehydes are formed chemically bymeans of intermediates which in some cases are free radicals. Similarundesired processes take place in the ageing of substances which consistof relative long carbon chains, for example rubber, plastics and mineraloil. As is known, for example, the lipid-soluble BHA (butylatedhydroxyanisole, cf. Merck-Index, tenth edition, Rahway, USA, 1983 No.1521 page 215), the still better lipid-soluble BHT (butylatedhydroxytoluene, ibid, No. 1520), and the likewise lipid-soluble, butunstable, temperature- and light-sensitive vitamin E (ibid, No. 9832,page 1437) and the lipid-insoluble ascorbic acid (ibid, No. 846 page120) are used as preservatives.

The present invention relates to novel antioxidants having particularlyadvantageous effects in lipophilic medium. They are compounds of theformula I

    (A).sub.a (L)(X).sub.a,                                    (I)

in which

a, a', A, L and X have the following meaning:

a and a'=independently of one another the numbers 1 or 2,

A=an antioxidative component from the group comprising

A₁ --a chroman partial structure of vitamin E ##STR1## in which Q inthis and all following formulae represents a free valency (covalentsingle bond),

A₂ --an alkyl-substituted mono-, di- or tri-phenol radical ##STR2## inwhich

m=1 or 2,

n=1 or 2, and

m+n=3 or 4,

R¹ =an alkyl radical and/or alkoxy radical

and the total number of carbon atoms of the alkyl or alkoxy radical

or the alkyl and alkoxy radicals is a maximum of 8;

A₃ --a reductone radical ##STR3## in which

R² =H or a lower alkyl radical (preferably C₁ -C₄) and

R³ =H, COOR⁴ or CH₂ OR⁴

R⁴ =H or a lower alkyl radical (preferably C₁ -C₄)

A₄ --a 1,2-dithiacycloalkyl or 1,2-dithiacycloalkenyl radical having2-6, preferably 2-4 carbon atoms in the ring and the dithiol form ofthese radicals which has been reduced by hydrogenation

A₅ --an ascorbic acid (derivative) radical ##STR4## in which

E=O, S or NR⁹

R⁵ =H, EH, EQ or Q

R⁶ =H, EH, EQ--(L--X₁) or Q--(L--X₁)

R⁷ =H, EH, EQ, Q or one of the radicals mentioned under A₂ and A₃,

R⁸ =H, EH, Q--(L--X₁) or --PO(OR⁹)₂,

R⁹ =H, a lower alkyl radical (preferably C₁ -C₄) or Q,

and only 1 or 2--preferably 1--of the radicals R⁵ -R⁹ are identical to Qor contain Q,

L=a bridging member and

X₁ =a lipophilic component as defined below;

L=a bridging member, composed of one or more of the building blocks##STR5## in which

R¹⁰, R¹¹, R¹² =H, a lower alkyl radical (preferably C₁ -C₄) or Q,

R¹¹ can moreover also be --CO_(a) R¹⁰ (where a=1 or 2), and 2 radicalsof the type --O--, --S-- and/or --NR¹⁰ -- are separated from one anotherby at least 1 carbon or phosphorus atom;

X=a lipophilic component from the group comprising

X₁ --cholane derivative radicals ##STR6## in which

R¹³ =sec. C₄ H₉ (=cholestane, R¹¹ (see under L) or Q,

E=O, S, NR¹⁰ (R¹⁰ see under L), (α,β-OH,H) or (α,β-Q, H) and a doublebond can be present in the 4,5- or 5,6- or 7,8-position, and

X₂ --an alkyl or cycloalkyl radical or a fatty acid derivative radicalhaving up to 24 carbon atoms.

Among the components A, L and X, the following radicals are preferred:

for A₄ :

a radical of the following formulae in the dithia form (as in theformulae) or in the dithiol form which has been reduced byhydrogenation: ##STR7## in which

R¹⁴ =H or a lower alkyl radical (preferably C₁ -C₄),

and

R¹⁵ =--(CH₂)_(b) --Q

b=0-12, preferably 0-4.

In the case A₄.2, particularly preferably:

R¹⁴ =H and

R¹⁵ =--(CH₂)₄ --Q (=decarboxylipoic acid or -dihydrolipoic acid partialstructure). ##STR8## in which

R¹⁶ and R¹⁹ =independently of one another=H or a lower alkyl radical(preferably C₁ -C₄)

R¹⁷ =Q and

R¹⁸ =H, a lower alkyl radical (preferably C₁ -C₄), an acyl radicalOCOR¹⁹ or OR¹⁹

R¹⁹ =a lower alkyl radical (preferably C₁ -C₄) or Q.

A₄.4 a dithiothreitol or dithioerythritol partial structure ##STR9## inwhich

R¹⁹ has the same meaning as in 4.3. ##STR10## in which

R²⁰ =H or a lower alkyl radical (preferably C₁ -C₄) and

Y=H₂ or O.

For A₅ :

E=O

R⁵, R⁶ and R⁷ =independently of one another=OH or OQ,

R⁸ =H or Q,

where only 1 or 2 radicals R⁵ -R⁸ contain Q or are identical to Q (=anascorbic acid radical).

Other particularly preferred radicals A are: ##STR11##

With respect to the antioxidative effect, L is an inert, chemicallystable bridging member for linking A and X. Bridging members L whichcontain an ester bond are somewhat more sensitive to hydrolysis thanbridging members without an ester component. This has to be taken intoconsideration if the stabilizing lipids come into contact with acids oralkalis. For example, in the case of use as pharmaceuticals, thecleavage of the ester bond by enzymes at the pharmacological site ofaction may, however, also offer advantages in that the antioxidativecomponent is removed and concentrated exactly at the site of action.

L preferably has the following formula:

    L=M.sub.p {[--(CH.sub.2).sub.w --(G.sub.1).sub.x --(G.sub.2)].sub.v -(CH.sub.2).sub.y --(G.sub.3).sub.z --(G.sub.4).sub.p+1 }M.sub.p

in which

p, x and z independently of one another=0 or 1,

v, w and y independently of one another=0-4, and v+w+y+z=0-10, ##STR12##where R¹⁰ has the abovementioned meaning (=H, a lower alkyl radical orQ) and

2 of the radicals --O--, --S-- and/or --NR¹⁰ -- are separated from oneanother by at least 1 carbon atom.

L is particularly preferably a radical from the group comprising:##STR13##

Very particularly preferred bridging members L are: ##STR14##

X is preferably a radical from the following group:

X₁.1 cholesterol

X₁.2 cholestanol

X₁.3 cholic acid

X₁.4 desoxycholic acid

X₁.5 ursodesoxycholic acid

X₁.6 chenodesoxycholic acid and

X₂.1 CH₃ --(CH₂)_(t) --Q

X₂.2 Q--C(CH₃)₃

X₂.3 Q--CH(CH₂)_(d)

X₂.4 Q--C═C--(CH₂)₅ --CH₃

X₂.5 R¹⁰ --CO₂ --(CH₂)_(z) --Q

d=4-6

t=3-24, preferably 6-18,

z=0 or 1

Particularly preferred radicals X₁ are: ##STR15## and particularlypreferred radicals X₂ are: ##STR16##

PREPARATION OF THE COMPOUNDS OF THE FORMULA I

The compounds are prepared by processes which are generally known. Theindividual components A and X are employed free or protected, ifappropriate in the form of reactive derivatives. Linking to L is carriedout by means of a reactive derivative of L. In the case of the protectedcompounds, the protecting groups are removed again after the linking.

The process is represented more explicitly as described in theexperimental section.

The compounds of the formula I according to the invention can be used asantioxidants, for example, in the fat-, oil-, plastics- andrubber-processing industry (such as the foodstuffs, cosmetics,pharmaceuticals, rubber and mineral oil industry), as preservatives forfatty substances (lipids) or for polymeric long-chain carbon compounds.

As explained below, the in vivo oxidation of lipid components (forexample of blood fats or of lipids of the biomembranes) of the human oranimal body also has undesired consequences: important lipids, inparticular cholesterol, are transported in the blood with the aid of lowdensity lipoprotein (LDL). Under physiological conditions, the LDLinteracts with the blood vessel system in a controlled manner. It isabsorbed into the vessel wall via specific receptors in a regulatedprocess and there makes its lipid components available as energycarriers or as cell building blocks. If an insufficient antioxidativeprotective action is then present, for example in particular underhyperlipidemic conditions, oxidation of the blood lipids can occur. Theoxidized blood lipids, or LDL, are then absorbed from the vessel wallsunhindered while avoiding the specific LDL receptors, i.e. thecontrolled process of receptor regulation breaks down. In the course ofthese toxic processes, in which radical intermediates are involved inparticular, oxidation products of cholesterol having mutagenic andcell-toxic properties, for example, are formed (Proc. Natl. Acad. Sci.USA 81 (1984) 4198-4202), while the unsaturated fatty acid radicals areoxidatively degraded to, for example, hydroxyalkenals having strongbiocidal effects. In the further course of the disease, the vesselregions attacked are considerably damaged by so-called foam cellformation with the participation of macrophages. Proliferation of thesmooth vessel musculature occurs and finally the formation ofatherosclerotic plaques which constrict the blood vessel. Blood clotscan collect there and finally an infarct can lead to permanent damage orto the death of the patient. These pathological processes cannot becompletely prevented alone by dietetic measures for the reduction of theblood lipid level. The medicinal reduction of the blood lipid level isindeed prior art, but has the disadvantage that it intervenes in thecomplex lipid metabolic processes. Under physiological conditions, thesemetabolic processes are in an exactly balanced equilibrium. An influenceon this equilibrium, in particular over a relatively long period, willinevitably also lead to undesired biological reactions. Undesired sideeffects of lipid-reducing medicaments, such as clofibrate or nicotinicacid, are listed, for example, in Meyler's Side Effects of Drugs, 10thedition, 1984, Elsevier Amsterdam--New York--Oxford.

Because of their protective action which is compartmentalized in thelipids, the lipid-soluble antioxidants according to the invention areadvantageously suited for the prevention and treatment of disorders inwhich (for example free radical) oxidation processes in the lipid mediumplay a role, in particular for the prevention and treatment of theprocesses described in disorders of the vessel wall. Owing to theirparticular antioxidative properties, the substances according to theinvention can also be used in other medical problems in whichbioradicals are involved. These include, for example, inflammatoryprocesses, in particular chronic inflammations such as rheumatism orarthritis, defective circulation as a result of, for example, cerebraldamage, such as stroke, and death of nerve cells (Alzheimer's disease),peripheral vascular diseases, such as thromboses and atherosclerosis,but also undesired mutagenic, cell-toxic and carcinogenic effects as aresult of light or radiation or asa result of chemicals, for examplecancer therapeutics, such as adriamycin, as well as reperfusion damage,which can occur after opening vascular occlusions, but also after organand tissue transplants, or after overcoming hypoxic conditions, forexample in neonatal medicine. In addition, the compounds according tothe invention are also suitable for curing liver damage.

For clinical therapeutic use, the antioxidants according to theinvention can also be present in the form of prodrugs, for example inthe form of their salts, from which the active compound is only formedin vivo. Metal cations which can be used are, for example, those of thealkali metals such as lithium, sodium and potassium, and of the alkalineearth metals such as magnesium and calcium, but also cationic formswhose metals, such as aluminum, zinc and iron are optionally chelatedwith citric acid or ethylenediaminetetraacetic acid and the like. Aminecations are those of primary, secondary or tertiary amines such as thealkylamines, for example mono-, di- and trimethyl; or -ethyl-, -propyl-,-isopropyl-, -butyl-, -isobutyl-, -t-butyl-, and N-(methylhexyl)-,benzyl-β-phenylethylamine, ethylenediamine, diethylenetriamine,pyrrolidine, piperidine, morpholine, piperazine, mono-, di- andtriethanolamine, ethyldiethanolamine, N-butylethanolamine,tris(hydroxymethyl)aminomethane and the like. Suitable amine salts are,for example, those of tryptamine, cysteine and the basic amine salts oflyeins and arginine. Suitable quaternary ammonium cations are, forexample, tetramethylammonium and benzyltrimethylammonium. These cationscan also be used for salt formation of the anionic forms of thecompounds according to the invention, while chloride and fluoride arepreferred for salt formation with the cationic forms.

PREPARATION OF ANTIOXIDATIVE COMPOSITIONS AND OF PHARMACEUTICALS

The compounds according to the invention are added to the lipids to beprotected in a customary manner. The amount of the antioxidant accordingto the invention added can vary within wide ranges. As is explained inthe experimental section, highly concentrated antioxidant/lipidsolutions can in particular be prepared. Stabilized preparations of thistype can then be processed in a large number of ways, for example inair, and then diluted again. After dilution, elastomers, rubber,plastics, fat and oils in general contain up to 1 percent by weight ormore of the antioxidants described above, although an addition of 0.1 %may be sufficient. For fats and oils which are used for human nutrition,0.5 percent by weight, preferably 0.005-0.03 percent by weight of theantioxidant according to the invention is used. Said mixture ratios canalso be used for the production of liposomes. For use as pharmaceuticalsfor the prophylaxis and for the treatment of hyperlipidemic andthrombotic peripheral and cerebral diseases, in particular vasculardiseases in humans and animals, the dosage necessary depends on thenature and severity of the disease, or on the animal species to betreated, but also on the age, weight and state of health of the patient.For humans, a dosage of 0.05 mg or 1 mg to 100 mg/day, in particular forintramuscular and intravenous dosage, may already be sufficient, the useof up to 200 mg or 500 mg/day, however, leading to a higher potency.Oral, peroral, rectal or (trans)dermal ministration which, however, maymake substantially higher dosages up to over 2.5 g/day necessary,although as a rule 50 mg to 800 mg/day are sufficient, is particularlysimple. Said dosages can be administered either as a single dose perday, but also twice or three times to eight times daily incorrespondingly reduced dose units.

The pharmaceutical preparations for said administrations are preparedaccording to the prior art. The active compounds according to theinvention can be present as a powder, gel, emulsion, dispersion orsolution and are divided into portions, for example dropwise or by thespoonful, or as the contents of capsules (including microcapsules andliposomes), it being possible, however, when using capsules or liposomesfor the shell also to assume the function of the active compoundcarrier. Dose units in the form of solid pharmaceutical forms, such astablets (including coated tablets and pills), or suppositories can beprepared by customary methods such as pressing, dipping or fluidized bedmethods, or pan coating and contain carriers and other customaryauxiliaries, such as gelatine, agarose, starch, for example potato, cornor wheat starch, cellulose, such as ethyl cellulose, silica, varioussugars, such as lactose, magnesium carbonate and/or calcium phosphates.The coating solution is usually composed of sugar and/or starch syrupand usually additionally contains gelatine, gum arabic,polyvinylpyrrolidone, synthetic cellulose esters, surface-activesubstances, plasticizers, pigments and similar additives correspondingto the prior art. Any customary flow-regulating agent, lubricant orglidant, such as magnesium stearate, and mold-release agents can be usedfor the production of the pharmaceutical forms. The active compounds,for example, can also be bound to ion exchangers (for examplepolystyrenedivinylbenzenesulfonic acid) or adsorbed on sustained releasematerial or incorporated into the sustained release material (forexample those based on cellulose or polystyrene resin, for examplehydroxyethylcellulose). Sustained release of the active compounds canalso be achieved by providing the layer concerned with customary gastricjuice-insoluble coatings.

The outstanding antioxidative properties of the lipophilic compoundsaccording to the invention are shown in the experimental section, inparticular also in comparison to antioxidants according to the priorart.

PREPARATION EXAMPLES

The following compounds of the formula I were prepared; if in theindividual compound formulae there is nothing or nothing else on thecarbon atoms, the possible free valencies are saturated with hydrogenatoms:

1) N-<3-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbamoyl)-propyl>cholicacid amide ##STR17##

2)N-<3-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbamoyl)-propyl>desoxycholicacid amide ##STR18##

3)(30)-2-[N-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbamoyl)aminoethyl]-3.beta.,7α,12α-cholicacid ##STR19##

4) N-Hexyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide ##STR20##

5)N-(3-Heptanamidopropyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide##STR21##

6) N-Octadecyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide##STR22##

7)N-(3-Hexadecanamidopropyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide##STR23##

8) Cyclohexyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide##STR24##

9)N-(3-Octadecanamidopropyl)-4-hydroxy-3-isopropyl-5-tert.-butylcarboxamide##STR25##

10) 4-[2-(5-Cholesten-3β-yloxy)-ethoxycarbonyl]-2,6-di-tert.-butylphenol##STR26##

11)3-[2-(5-Cholesten-3β-yloxy)ethoxycarbonyl]-1,5-dihydroxy-6-methoxyphenol##STR27##

12)4-[2-(5-Cholesten-3β-yloxy)-ethoxycarbonyl]-2,6-dihydroxy-1-methoxyphenol##STR28##

13) 4-<2-(5-Cholesten-3β-yloxy)-ethoxymethyl>-2,6-di-tert.-butylphenol##STR29##

14) 4-[2-(Cholestan-3β-yloxy)-ethoxymethyl]-2,6-di-tert.-butylphenol##STR30##

15) 4-[2-(Cholestan-3β-yloxy)-ethoxymethyl]-2-tert.-butyl-6-methylphenol ##STR31##

16) 4-[2-(7α,12α-Trihydroxy-5β-cholanicacid-3β-yloxy)-ethoxymethyl]-2,6-diisopropylphenol ##STR32##

17) 2,6-Di-tert.-butyl-4-<7-nonynoyl>phenol ##STR33##

18) Ethyl 2-(3,5-di-tert.-butyl-4-hydroxybenzyl)-3-oxodocosanoate##STR34##

19) 5-[2-(3,5-Di-tert.-butyl-4-hydroxyphenyl)-1,3-dithian-4-yl]-valericacid ##STR35##

20) tert.-Butyl 6,8-bis((3,5-di-4-hydroxy-phenyl)-methyl-thio)octanoate##STR36##

21) 2(R,S)-1-O-(3,5-Di-tert.butyl-4-hydroxybenzyl)-3-O-octadecylglycerol##STR37##

22)2(R,S)-2-O-(3,5-Di-tert.-butyl-4-hydroxybenzoyl)-1-O-octadecylglycerol##STR38##

23)2(R,S)-1-O-(3,5-Di-tert.-butyl-4-hydroxybenzoyl)-3-O-octadecylglycerol##STR39##

24) Ethyl 2-(3,5-di-tert.-butyl-4-hydroxybenzyl)-3-hydroxydocosanoate##STR40##

25) 1,3-Dihydroxy-2-(3,5-di-tert.-butyl-4-hydroxybenzyl)-docosane##STR41##

26)5(R,S)-(3,5-Di-tert.-butyl-4-hydroxybenzyl)-2,2-dimethyl-6(R,S)-nonadecyl-1,3-dioxolane##STR42##

27) Ethyl 2-(3,5-di-tert.-butyl-4-hydroxybenzyl)-3-hydroxydocosanoate##STR43##

28) Ethyl(E,Z)-2-(3,5-di-tert.-butyl-4-hydroxybenzylidene)-3-oxodocosanoate##STR44##

29)2-O-Octoadecyl-3-O-(3,5-di-tert.-butyl-4-hydroxyphenylmethyl)ascorbicacid ##STR45##

30) 2-Cholesteryloxyethyl3'-keto-4',5'-dihydroxy-1',2',6'-trihydrobenzoate ##STR46##

31) 4-Octadecoxy-5-hydroxy-3-keto-4,5-dehydrocyclohexanecarboxylic acid##STR47##

32) Octadecyl 3-keto-4,5-dihydroxy-1,2,6-tri-hydrobenzoate ##STR48##

33) 2-O-(2-Cholesteryloxyethyl)ascorbic acid ##STR49##

34) 6-O-Octadecanoyl-2-O-(O*,O*-diethylphosphoryl)-ascorbic acid##STR50##

35) 5-O,6-O-Dioctadecanoyl-2-O-(O*,O*-diethylphosphoryl)-ascorbic acid##STR51##

36) 1,3-Bis<2-(2-O-ascorbyloxy)ethoxy>-2-octadecylpropane ##STR52##

37) Di-(2-O-ascorbyl) octadecylphosphonate ##STR53##

38) 4,5-Dithiacyclohexyl 1,2-distearate ##STR54##

39) 4,5-Dithiacyclohexyl 1,2-distearate, reduced ##STR55##

40) 4,5-Dithia-2-hydroxycyclohexyl stearate ##STR56##

41) 4,5-Dithia-2-hydroxycyclohexyl stearate, reduced ##STR57##

42) 2-Hydroxy-4,5-dithiacyclohexylursodesoxycholate ##STR58##

43) 2-Hydroxy-4,5-dithicyclohexyldesoxycholate, reduced ##STR59##

44) Bis(cholesteryl 6(R,S)-(2',3'-dimercaptosuccinate), oxidized##STR60##

45) Cholesteryl 6(R,S)-(2',3'-dimercaptoethylsuccinate) ##STR61##

46) Cholesteryl 6(R,S)-dihydrolipoate ##STR62##

47) N-2-(5-Cholesten-3α-yloxy)ethyldihydrolipoic acid amide ##STR63##

48) N-<3-(6,8-Dimercaptooctanoylamino)propyl>desoxycholic acid ##STR64##

49) N-Octadecyl-DL-dihydrolipoic acid amide ##STR65##

50) Octadecyl DL-dihydrolipoate ##STR66##

51) Octadecyl DL-α-lipoate ##STR67##

52) N-Octadecyl-DL-α-lipoic acid amide ##STR68##

53) Cholesteryl 6(R,S)-lipoate ##STR69##

The preparation of these compounds is now described in the following;starting materials and intermediates are denoted by numbers from 70upwards.

EXAMPLE 1 ##STR70##

a) 1.0 g (4.0 mmol) of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Aldrich) was dissolved in 50 ml of THF/2.8 mlof triethylamine and 0.77 ml (8.0 mmol) of ethyl chloroformate was addedat 0° C. The mixture was stirred at 0° C. for 15 min and at roomtemperature for 30 min. 1.86 g (4.0 mmol) of solid amine 70 [prepared byreaction of methyl chlorate with 1,3-diaminopropane (in excess withoutsolvent), 5 h, reflux] were then added and the mixture was stirred atroom temperature for 3 h. The reaction mixture was poured into water andextracted using ethyl acetate (3×), and the combined organic phases weredried (MgSO₄) and concentrated. Chromatography on silica gel (ethylacetate/methanol=10:1) gave 2.11 g of a white solid. m.p. 102°-105° C.

b) To liberate the phenol, 2.11 g (2.74 mmol) of the product obtained bya) were dissolved in 50 ml of methanol and 3.8 g (27 mmol) of potassiumcarbonate were added. The mixture was heated under reflux for 1 h andthe solvent was largely evaporated. The residue was thoroughly stirredwith water and the product was filtered off with suction. Chromatographyon silica gel (CH₂ Cl₂ /MeOH=10:1.5) gave 1.5 g (79 %) of Example 2,m.p. 135°-140° C. C₄₁ H₆₄ N₂ O₇ (696), MS¹) (FAB²)), 3-NBA³) /Li)I: 703(M⁴) +Li⁺

Abbreviations familiar to the person skilled in the art:

¹) MS=Mass spectrum

²) FAB=Fast atom bombardment

³) 3-NBA=

⁴) M⁺ =Molecular ion

The examples in Table I were obtained completely analogously to Example1.

                                      TABLE 1                                     __________________________________________________________________________     ##STR71##                                                                    Ex-                                                                           ample                                                                             R                                                MS                       __________________________________________________________________________         ##STR72##                                       C.sub.41 H.sub.64                                                             N.sub.2 O.sub.6                                                               (608) MS (FAB): 681      3                                                                                  ##STR73##                                       C.sub.40 H.sub.61                                                             NO.sub.8 (683) MS                                                             (FAB, 3'NBA/ LiJ):                                                            696 (M + 2LilH), 690                                                          M + Li)                  4   (CH.sub.2).sub.5CH.sub.3                         C.sub.20 H.sub.32                                                             NO.sub.3 (333)                                                                MS (DCI): 334                                                                 (M + H)                  5                                                                                  ##STR74##                                       C.sub.24 H.sub.38                                                             N.sub.2 O.sub.4                                                               (418) MS (FAB): 419      6   (CH.sub.2).sub.17CH.sub.3                        C.sub.32 H.sub.55                                                             O.sub.3 N (501)                                                               MS (DCI): 502            7                                                                                  ##STR75##                                       C.sub.33 H.sub.56                                                             N.sub.2 O.sub.4                                                               (544) MS (DCI): 545      8                                                                                  ##STR76##                                       C.sub.20 H.sub. 29                                                            NO.sub.3 (331) MS                                                             (DCI):                   __________________________________________________________________________                                                         332                  

EXAMPLE 13 ##STR77##

500 mg (1.16mmol) of steroid alcohol ○71 (J. Med. Chem. 1980, 1185)dissolved in a little THF were added dropwise to 61 mg (1.27 mmol) ofsodium hydride in 5 ml of THF/5 ml of DMF. The mixture was then warmedto 50°-60° C. for 30 min. 180 mg (0.6 mmol) of solid bromide ○72 werethen added at 0° C. After 1 h at room temperature, a further 80 mg ofbromide were added. The mixture was stirred at room temperature for afurther 1 h and poured into water, and the aqueous phase was acidifiedusing 1N HCl and extracted using ether (3×). The combined ether phaseswere washed with satd. NaHCO₃ solution and dried (MgSO₄). Evaporationand chromatography on silica gel (cyclohexane/ethyl acetate=9:1) gave240 mg of Example 13 after crystallisation from methanol. m.p. 108°-110°C. C₄₄ H₇₂ O₃ (648), MS FAB, 3-NBA/LiI): 655 (M+Li⁺)

The examples in Table 2 were obtained in analogy to Example 13 byalkylation of the appropriate alcohols (prepn. see below) with thebromide 72.

                  TABLE 2                                                         ______________________________________                                         ##STR78##                                                                    Example R                   MS                                                ______________________________________                                        21                                                                                     ##STR79##          C.sub.36 H.sub.66 O.sub.4 (562) MS (DCI): 563                                 M + H.sup.+)                                      Starting material: Helv. Chimica Acta 71, 274 (1988)                          29                                                                                     ##STR80##          C.sub.39 H.sub.65 O.sub.7 (645) MS (DCI): 646                                 M + H.sup.+)                                      Starting material: cf. J. Med. Chem. 31, 793 (1988)                           ______________________________________                                    

EXAMPLE 20 ##STR81##

Example 20 was obtained from t-butyl dihydrolipoate and 2 equivalents ofbromide 72 in the same manner. t-Butyl dihydrolipoate was obtainedaccording to Examples 46-50 and t-butyl lipoate according to Examples 53and 51. C₄₂ H₆₈ S₂₀ O₄ (700), MS (DCI): 701 (M+H⁺)

EXAMPLE 17 ##STR82##

a) 21 ml (33.6 mmol) of n-BuLi (hexane) were added dropwise under anargon atmosphere between -20° C. and -40° C. to a solution of 5 ml (33.8mmol) of n-octyne. After 1 h, 2.8 g (12 mmol) of3,5-di-tert.-butyl-4-hydroxybenzaldehyde (Aldrich), dissolved in alittle THF, were added dropwise. The mixture was stirred overnight atroom temperature. The reaction mixture was poured into 2N HCl/ice andextracted using ether (3×). The combined organic phases were washed withsaturated sodium hydrogen carbonate solution (2×) and dried (MgSO₄).Evaporation gave 4.96 g (quant.), which was further reacted according tob).

b) 4.96 g of the alcohol obtained according to a) were dissolved in 45ml of dichloromethane and 4.66 g (21 mmol) of pyridinium chlorochromatewere added. After 2 H at room temperature, the mixture was diluted withether and the solution was decanted. Filtration through silica gel(cyclohexane/ethyl acetate=3:1) gave 2.82 g (57%) of Example 17. m.p.63°-65° C.

EXAMPLE 72 ##STR83##

44.8 g (0.2 mol) of 2,6-di-tert.-butyl-p-cresol, 35.6 g (0.2 mol) of NBSand 400 mg of AIBN in 500 ml of carbon tetrachloride were heated underreflux for 2 h. After cooling, the mixture was filtered off andevaporated, Yield 63.9 g (quantitative) of Example 72.

EXAMPLE 18 ##STR84##

3.82 g (10 mmol) of keto ester 73 (keto ester 73 was obtained by dianionalkylation of ethyl aceto acetate with octadecyl iodide. NaH and bullwere used as bases) in 15 ml of THF were added dropwise at 0° C. undernitrogen to 1.09 g (25 mmol) of sodium hydride in 5 ml of TEE. Themixture was stirred at 0° C for 30 min and 3.0 g (10 mmol) of bromide72, dissolved in 10 ml of THF, were then added at this temperature.After 2 days at room temperature, the reaction mixture was poured intocold saturated ammonium chloride solution and extracted using ether(3×). The combined organic phases were dried (MgSO₄) and evaporated.Prep. HPLC (cyclohexane/ethyl acetate=12:1) gave 3.9 g (65 %) of Example18. C₃₉ H₆₈ O₄ (600), MS (DCI): 601 (M+H⁺)

EXAMPLE 19 ##STR85##

a) 100 mg (0.48 mmol) of DL-α-lipoic acid were dissolved in 2 ml of0.25N aqueous sodium hydrogen carbonate solution and 20 mg of sodiumborohydride were added. The mixture was stirred at 0° C. for 30 min, 2ml of toluene were added and it was adjusted to pH 1 using 2Nhydrochloric acid. The organic phase was separated off and evaporated.

b) The residue obtained according to a) was taken up in 5 ml ofdichloromethane and 114 mg (0.48mmol) of3,5-di-tert.-butyl-4-hydroxybenzaldehyde were added. 60 μl (0.48mmol) ofboron trifluoride etherate were then added and the mixture was stirredat room temperature for 1 h. The reaction mixture was partitionedbetween water and ethyl acetate. The organic phase was separated off,dried (MgSO₄) and evaporated. Chromatography on silica gel(cyclohexane/ethyl acetate=2:1) gave 135 mg (66%) of Example 19. m.p.67°-68° C. C₂₃ H₃₆ O₃ S₂ (424).

EXAMPLE 24 ##STR86##

500 mg (0.83 mmol) of Example 18 were dissolved in 15 ml of ethanol and112 mg (2.5 mmol) of sodium borohydride were added at 0° C. Afterstirring at 0° C. for 1.5 h, the reaction mixture was poured into 50 mlof cold, saturated ammonium chloride solution and extracted using ether(3×). The combined ether phases were dried (MgSO₄) and evaporated.Chromatography on silica gel (cyclohexane/ethyl acetate=4:1) gave 480 mg(95%) of Example 24. C₃₉ H₇₀ O₄ (602), MS (FAB, 3-NBA/LiI), 609 (M+Li⁺)

EXAMPLE 25 ##STR87##

500 mg (0.83 mmol) of Example 18, dissolved in 5 ml of THF, were addeddropwise at 0° C. under nitrogen to 65 mg (1.67 mmol) of lithiumaluminum hydride in 10 ml of THF. The mixture was stirred at roomtemperature for 2 h. The reaction mixture was poured into saturatedaqueous ammonium chloride solution and extracted using ether (3×). Thecombined ether phases were dried (MgSO₄) and evaporated. Chromatographyon silica gel (cyclohexane/ethyl acetate=1:1) gave 460 mg of Example 25.m.p. 77°-78° C. C₃₇ H₆₈ O₃ (560), MS (FAB, 3-NBA/LiI): 567 (M+Li⁺).

EXAMPLE 26 ##STR88##

168 mg (0.3 mmol) of Example 25 were dissolved in10 ml of acetone and0.5 ml of acetyl chloride was added at room temperature. The mixture wasstirred at room temperature for 1 h, ether was added and the solutionwas washed with saturated aqueous sodium hydrogen carbonate solution.Drying (MgSO₄), evaporation and chromatography of the residue on silicagel (cyclohexane/ethyl acetate=5:1) gave 164 mg (91%) of Example 26. C₄₀H₇₂ O₃ (600), MS (DCI): 600 (M+) .

EXAMPLE 27 ##STR89##

150 mg (0.25 mmol) of Example 24 were dissolved in 5 ml of ethanol and5.0 ml of 0.1N sodium hydroxide solution were added. The mixture washeated under reflux for 8 h. The reaction mixture was poured ontoice/HCl and extracted using ether (3×). The combined organic phases werewashed with saturated sodium chloride solution (1×) and dried.Evaporation gave the free acid. 131 mg of the free acid were dissolvedin ethanol and 2.23 ml of 0.1N aqueous sodium hydroxide solution wereadded. The solution was evaporated several times with the addition oftoluene. 130 mg of sodium salt of Example 27 were obtained.

EXAMPLE 28 ##STR90##

1.0 g (2.61 mmol) of keto ester 73, and 613 mg (2.61 mmol) of3,5-di-tert.-butyl-4-hydroxybenzaldehyde (Aldrich) were heated underreflux for 3 days in 10 ml of pyridine with the addition of 93 μl (1.2mmol) of glacial acetic acid and 10 μl (0.1 mmol) of piperidine. Themixture was diluted with toluene and washed with semi-saturated sodiumchloride solution and dried (Na₂ SO₄). Evaporation and chromatography onsilica gel (cyclohexane/ethyl acetate=7:1) gave 740 mg (47%) of Example28. C₃₉ H₆₆ O₄ (598), MS (DCI): 599 (M+H⁺)

EXAMPLE 33 ##STR91##

33 was prepared from Examples 74 and 71 in analogy to Examples 82, 75(procedure b) and 34. C₃₅ H₅₆ O₇ (588), MS (FAB): 601 (M+2Li-H),m.p.>160° (dec.)

EXAMPLE 75 ##STR92##

a) 44.9 g (0.146 mol) of alcohol 74 were dissolved in 300 ml ofdichloromethane and 103 ml (0.733 mol) of triethylamine were added at 0°C. 23.2 ml (0.161 mol) of diethyl chlorophosphate were added dropwise at0° C. and the mixture was stirred at 0° C. for 3 days. The reactionmixture was poured into saturated aqueous ammonium chloride solution andextracted using ether (3×). The combined organic phases were dried(MgSO₄) and evaporated. Chromatography on silica gel (cyclohexane/ethylacetate=3:2) gave 18.1 g (28%). Rf (cyclohexane/ethyl acetate=1:1):0.20.

b) To cleave the acetonide, the 18.1 g obtained according to a)dissolved in 50 ml of ethanol were added to 170 ml of ethanolic HClprepared by dropwise addition of 3.0 ml of acetyl chloride to 167 ml ofethanol] and the mixture was heated under reflux for 2 h. The solventwas evaporated and the residue was filtered through Florisil (ethylacetate). After evaporating, 14.1 g (85%) of diol 75 were obtained. Rf(ethyl acetate): 0.33.

EXAMPLES 76 AND 77 ##STR93## EXAMPLE 76

2.01 g (5 mmol) of diol 75 were dissolved in 20 ml of pyridine and 4.8 g(15 mmol) of stearoyl chloride were added at room temperature. Themixture was stirred for 30 min and poured into cold 2N hydrochloricacid, and the product was filtered off with suction. Chromatography onsilica gel (cyclohexane/ethyl acetate=7:3) gave 4.11 g (88%) of Example76.

EXAMPLE 77

Example 77 was obtained completely analogously to 76 using oneequivalent of stearic acid.

EXAMPLE 34 ##STR94##

540 mg (0.81mmol)of Example 77 in 10 ml of ethanol were hydrogenated atnormal pressure and room temperature using 100 mg of Pd/C (10%). Thecatalyst was filtered off, the filtrate was evaporated and the residuewas triturated with n-pentane. Yield 335 mg (71%) of Example 34. m.p.84°-85° C. C₂₈ H₅₁ O₁₀ P (578): MS (FAB, 3-NBA/LiI): 585 (M+Li⁺), 591(M+2Li-H).

EXAMPLE 35 ##STR95##

Example 35 was obtained completely analogously to Example 34.m.p.88°-90° C. C₄₆ H₈₅ O₁₁ (845), MS (FAB, 3-NBA/LiI): 851 (M+Li⁺), 857(M+2Li-H).

EXAMPLE 78 ##STR96## EXAMPLE 81 FROM 80 (a)

5 g (0.012 mo1) of diol 81 were dissolved in 25 ml of dichloromethane,and 1.1 ml (0.012 mol) of dihydropyran and 500 mg of pyridiniump-toluenesulfonate were added. After stirring at room temperature for 6h, the mixture was diluted with 100 ml of ether and washed withsaturated sodium chloride solution (2×). The organic phase was dried andevaporated. Chromatography on silica gel (ethyl acetate/cyclohexane=1:1)gave 3.1 g (52%) of Example 81 in addition to 1.53 g of bis-THP etherand 1.0 g of starting material.

EXAMPLE 82 FROM 81 (b)

2.75 g (5.5mmol) of Example 81, 1.68 g (5.5 mmol) of 74, 1.44 g (5.5mmol) of triphenylphosphine and 1.1 ml (5.5 mmol) of diisopropylazodicarboxylate in 25 ml of THF were stirred at room temperature for 1h. After evaporation, the residue was chromatographed on silica gel(ethyl acetate/cyclohexane=1:2). Yield 2.3 g (53%) of Example 82.

EXAMPLE 83 FROM 82 (c)

70 mg of pyridinium p-toluenesulfonate were added at room temperature to2.2 g (2.8 mmol) of Example 82 in 50 ml of ethanol and the mixture wasstirred at 50° C. for 4 h. The reaction mixture was evaporated and theresidue was partitioned between ether and semisaturated NaCl solution.Drying of the organic phase (MgSO₄) and evaporation gave, afterchromatography on silica gel (cyclohexane/ethyl acetate=1:1), 1.3 g(67%) of Example 83.

EXAMPLE 78 FROM 83 (d)

Analogously to Example 82 (b).

EXAMPLE 79 ##STR97## EXAMPLE 84 a)

17.5 g (46 mmol) of octadecyl iodide and 8.0 ml (46 mmol) of triethylphosphite were heated under reflux for 2 h. Chromatography on silica gel(ethyl acetate) gave 12.2 g (31 mmol, 68%) of Example 84.

EXAMPLE 85 b)

The hydrolysis of 84 to give 85 was carried out by boiling withconcentrated hydrochloric acid for several hours (TLC checking) and theproduct was worked up in the customary manner.

EXAMPLE 86 (c)

1 g of acid Example 85 was boiled under reflux for 2 h in 20 ml ofthionyl chloride with the addition of a drop of DMF. Concentration andevaporation several times with toluene gave the acid chloride 86.

EXAMPLE 79 (d)

The reaction was carried out analogously (2 equivalents of 74) toExample 75 (procedure a). Extractive work-up and chromatography onsilica gel (cyclohexane/ethyl acetate=3.2, 1:1) gave Example 79. Yield54%.

EXAMPLES 36 AND 37

Example 36 was obtained from Example 78 and Example 37 from Example 79analogously to Example 75 (procedure b) and Example 34.

EXAMPLE 36 ##STR98##

H₃ C--(CH₂)₁₇ --CH--(CH₂ OCH₂ CH₂ --OR)₂

m.p. >120° C. (dec.)

C₃₇ H₆₄ O₁₄ (732), MS (FAB, 3-NBA/LiI): 751 (M+3Li-2H)

EXAMPLE 37 ##STR99##

m.p. 72°-75° C.

C₃₀ H₅₁ O₁₃ P (650), MS (DCI): 651 (M+H⁺)

EXAMPLES 46-55

a) Preparation of lipoic acid esters ##STR100##

Lipoic acid and the appropriate alcohol are initially introduced intodichloromethane in a molar ratio of 1:1. 1 equivalent of4-dimethylaminopyridine and then 1 equivalent ofdicyclohexylcarbodiimide are added at room temperature. The mixture isstirred at room temperature for 2-5 h and evaporated, the produced istaken up in a suitable solvent (the urea for the largest part usuallyremains undissolved) and the solution is chromatographed on silica gel.

The lipoic acid esters shown in Table 3 were obtained by the process.

                                      TABLE 3                                     __________________________________________________________________________     ##STR101##                                                                   Example                                                                            R                          MS                                            __________________________________________________________________________    53                                                                                  ##STR102##                C.sub.35 H.sub.58 O.sub.2 S.sub.2 (574)                                       MS (DCI): 575 (M + H.sup.+)                   51   (CH.sub.2).sub.17 CH.sub.3 C.sub.26 H.sub.50 O.sub.2 S.sub.2 (458)                                       MS (DCI): 458                                 __________________________________________________________________________

b) Preparation of lipoic acid amides ##STR103##

Lipoic acid and the corresponding amine are initially introduced intodichloromethane in a molar ratio of 2:1 or 1:1. 1 equivalent of4-dimethylaminopyridine and then 1 equivalent ofdicyclohexylcarbodiimide are added at room temperature. The mixture isstirred at room temperature for 2-5 h and evaporated, the produce istaken up in a suitable solvent (the urea for the largest part usuallyremains undissolved) and the solution is chromatographed on silica gel.

The lipoic acid amides shown in Table 4 were obtained according to thisprocess.

                                      TABLE 4                                     __________________________________________________________________________     ##STR104##                                                                   Example                                                                            R                                  MS                                    __________________________________________________________________________    54                                                                                  ##STR105##                        C.sub.37 H.sub.63 NO.sub.2                                                    S.sub.2 (618) MS (FAB, 3-NBH/                                                 LiJ): 624 (M + Li.sup.+)              __________________________________________________________________________

(Starting amine by Gabriel synthesis from 71 via the correspondingiodide) ##STR106##

c) Reduction of lipoic acid derivatives to dihydrolipoic acidderivatives ##STR107##

1 part of lipoic acid derivative is initially introduced in methanol/THFmixtures (preferably 1:2) and 2-3 equivalents of sodium borohydride areadded at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for2-3 h, the mixture is poured into semisaturated ammonium chloridesolution and extracted using ethyl acetate (2×). The combined organicphases are dried (MgSO₄) and evaporated. The product is dried in a highvacuum.

The examples of Table 5 were prepared by this process.

                                      TABLE 5                                     __________________________________________________________________________     ##STR108##                                                                   Example                                                                            R                                   MS                                   __________________________________________________________________________         X = O                                                                    46                                                                                  ##STR109##                         C.sub.35 H.sub.60 O.sub.2                                                     S.sub.2 (576) MS (FAB, 3-NBA/                                                 LiJ): 583 (M + H.sup.+)              50   (CH.sub.2).sub.17 CH.sub.3          C.sub.26 H.sub.52 O.sub.2                                                     S.sub.2 (460)                                                                 MS (DCI): 461                                                                 (M + H.sup.+)                             X = NH                                                                   47                                                                                  ##STR110##                         C.sub.37 H.sub.65 NO.sub.2 (619)                                              S (FAB, 3-NBA/ LiJ): 626 (M +                                                 Li)                                  48                                                                                  ##STR111##                         C.sub.35 H.sub.62 N.sub.2                                                     O.sub.4 S.sub.2 (638) MS (FAB,                                                3-NBA/ LiJ): 645 (M + Li.sup.+)      49   (CH.sub.2).sub.17 CH.sub.3          C.sub.26 H.sub.53 NOS.sub.2                                                   (459)                                                                         MS (DCI): 460                                                                 (M + H.sup.+)                        __________________________________________________________________________

LIPOPHILIC AND ANTIOXIDATIVE PROPERTIES Method I

Antioxidative radical scavenger properties by thediphenylpicrylhydrazine (DPPH) method:

The determination was carried out spectrophotometrically (PMQ4 fromZeiss, Oberkochen, FRG) by the method described in Smith and Reeves,Biochemical Pharmacology 36 (1987) pp. 1457-1460. The antioxidativeeffects of the preparations tested are shown in Table 1. The measurementis the rate constant determined graphically (concentration versusconversion rate) in a known manner, measured in absolute ethanol. Withthe exception of the oxidized mercaptans, all preparations investigatedin fact showed variously pronounced, but clear antioxidative action.

Method II

Use as an additive in frying fat:

Samples of commercially available German non-blended butter were meltedand in each case 1% (weight/weight) of BHT (=butylated hydroxytoluene)or 2,6-di-tert.-butyl-4-(7-nonynoyl)-phenol (=compound according toExample 17] or ethyl2-(3,5-di-tert.-butyl-4-hydroxybenzyl)-3-oxo-docosanoate (=compoundaccording to Example 18) or N-octadecyl-DL-α-lipoic acid amide(=compound according to Example 52) was added and the mixture was usedin the customary manner as frying fat. After the frying procedure, thesample containing BHT was transformed into a viscous, dark brownmaterial, while the use of said comparison preparations led to asubstantially lower color change. The better protective action of thecomparison preparations probably comes about as a result of theirlipophilic side chains and, therefore, improved lipophilic interaction.The advantageous action of N-octadecyl-DL-α-lipoic acid amide isparticularly surprising, although this preparation has no recognizableantioxidative component.

Method III

Lipid solubility of the compounds and protective action.

a) Preparation of olive oil or aqueous solutions.

1 ml of olive oil or 1 ml of double-distilled water (or dilute NaOHpH=7.6) was added to I mg or 10 mg or 50 mg of the respective compoundat 37° C. and it was checked whether a clear solution was obtained. Theoptionally centrifuged and decanted olive oil solutions were heated for5 minutes using a Bunsen burner and the degree of browning of the oliveoil was determined. Under these conditions, the oil without additive andwithout protective action becomes distinctly dark brown. After additionof antioxidant and in the case of good protective action, the oilbecomes only dark yellow to light brown. Samples having poor protectiveaction are given a (*) in the table (see below).

The extremely high solubility (>1:1) of the antioxidants according tothe invention in molten cholesteryl palmirate at 85° C. is alsoadvantageous.

                  TABLE 1                                                         ______________________________________                                        Results                                                                                       Method I                                                                      Reaction                                                                      with DPPH Method III                                          Compounds       (rate     Solubility (mg/ml)                                  tested:         constant) Water     Olive oil                                 ______________________________________                                        Vitamin E analogues                                                           6-Hydroxy-2,5,7,8-tetra-                                                                      2.65      >10.0     <0.1                                      methylchroman-2-                                                              carboxylic acid.sup.(1)                                                       Vitamin E.sup.(1)                                                                             2.90      <0.1      >10.0                                     Cpd. acc. to Ex. 1                                                                            0.681     >0.1      >10.0                                     Cpd. acc. to Ex. 2                                                                            0.528     >0.1      >10.0                                     Cpd. acc. to Ex. 3        <0.1      >1.0                                      Vitamin E analogues                                                           6-Hydroxy-2,5,7,8-tetra-                                                                      2.65      >10.0     <0.1                                      methylchroman-2-                                                              carboxylic acid.sup.(1)                                                       Vitamin E.sup.(1)                                                                             2.90      <0.1      >10.0                                     Cpd. acc. to Ex. 4        >0.1      >10.0                                     Cpd. acc. to Ex. 5        <0.1      >10.0                                     Cpd. acc. to Ex. 6                                                                            0.254     <0.1      >10.0                                     Cpd. acc. to Ex. 7                                                                            0.355     <0.1      >10.0                                     Cpd. acc. to Ex. 8        <0.1      >10.0                                     Phenols                                                                       Gallic acid.sup.(1)       >10.0     <0.1                                      BHT.sup.(1)               <0.1      >10.0                                     Cpd. acc. to Ex. 13                                                                           0.061     <0.1      >50.0                                     Cpd. acc. to Ex. 17                                                                           0.004     < 0.1     >50.0                                     Cpd. acc. to Ex. 18       <0.1      >50.0                                     Cpd. acc. to Ex. 19                                                                           0.268     <0.1      >50.0                                     Cpd. acc. to Ex. 20       <0.1      >50.0                                     Cpd. acc. to Ex. 21                                                                           0.236     <0.1      >50.0                                     Cpd. acc. to Ex. 22                                                                           0.004     <0.1      >50.0                                     Cpd. acc. to Ex. 23                                                                           0.006     <0.1      >50.0                                     Cpd. acc. to Ex. 24                                                                           0.054     <0.1      >50.0                                     Cpd. acc. to Ex. 25                                                                           0.052     <0.1      >50.0                                     Cpd. acc. to Ex. 26                                                                           0.065     <0.1      >50.0                                     Cpd. acc. to Ex. 27       >10.0     >1.0                                      Cpd. acc. to Ex. 28       <0.1      >50.0                                     Cpd. acc. to Ex. 29                                                                           0.711     >1.0      >10.0                                     Ascorbic acid analog                                                          Ascorbic acid.sup.(1)                                                                         2.99      >10.0     <0.1                                      Ascorbyl palmitate.sup.(1)                                                                              <0.1      >0.1                                      Cpd. acc. to Ex. 34                                                                           0.052     <0.1      >1.0                                      Cpd. acc. to Ex. 35                                                                           0.053     <0.1      >1.0                                      Cpd. acc. to Ex. 37                                                                           1.13      >10.0     >1.0                                      Cpd. acc. to Ex. 33       <0.1      >1.0                                      Cpd. acc. to Ex. 36                                                                           0.242     >10.0     >10.0                                     Mercaptans                                                                    Dihydrolipoic acid,                                                                           3.147     >10.0     <0.1*                                     Na salt.sup.(1)                                                               Dithiothreitol.sup.(1)                                                                        5.632     >10.0     <0.1                                      Dithioerythritol.sup.(1)  >10.0     <0.1                                      2,3-Mercaptosuccinic acid.sup.(1)                                                                       >10.0     <0.1                                      Cpd. acc. to Ex. 46                                                                           0.440     <0.1      >50.0                                     Cpd. acc. to Ex. 47                                                                           0.075     <0.1      >50.0                                     Cpd. acc. to Ex. 48                                                                           0.337     <0.1      >50.0                                     Cpd. acc. to Ex. 49                                                                           0.243     <0.1      >10.0                                     Cpd. acc. to Ex. 50                                                                           0.248     <0.1      >50.0                                     Oxidized Mercaptans                                                           Lipoic acid, Na salt.sup.(1)                                                                  0.0       >10.0     <0.1*                                     Cpd. acc. to Ex. 51                                                                           0.0       <0.1      >50.0                                     Cpd. acc. to Ex. 52                                                                           0.0       <0.1      >10.0                                     Cpd. acc. to Ex. 53       <0.1      >50.0                                     ______________________________________                                         .sup.(1) = not according to the invention                                

Result:

In addition to the required lipid solubility, the antioxidants accordingto the invention show excellent antioxidative protective effects.

The findings of Table 1 were supplemented by the experimentaldetermination of the partition coefficient K_(d) (butanol/water methodaccording to Carney and Graham, Arzneim.-Forschung 35 (1985) 228-233),which confirmed the lipophilicity of the compounds.

It was also possible experimentally to extract virtually completely (toabout 100%) the compounds according to the invention from aqueoussolutions or suspensions (consisting of 1 mg of antioxidant/ml ofphysiological saline solution pH=7.6) by octanol.

Owing to its solubility properties, the compound according to Example 36is outstandingly suitable for use in aqueous oil emulsions.

Method IV Inhibition of the Oxidation of Lipids

Oxidation of 1-stearoyl-2-arachidonoylphosphatidylcholine (SA-PC) incyclohexane (37° C). 100 mcl of a SA-PC solution (10 mg/ml of CHCl₃)were evaporated by blowing (argon) and the residue was taken up in I mlof cyclohexane. After adding an Mount of antioxidant which would alsodissolve in olive oil (cf. Table 1), the absorption was measured at 234nm (Perkin Elmer 5528 spektrophotometer, Oberlingen, FRG) and thesolvent was then evaporated by blowing with air. After a further 24hours standing in an open vessel, the residue was again dissolved in 1ml of cyclohexane and the absorption at 234 nm was measured as ameasurement of the oxidized SA-PC.

Result

Owing to their good lipid solubility, it was possible to suppressvirtually completely the oxidation of SA-PC with 1 mg to 10 mg/ml of theantioxidants according to the invention in each case. It wassurprisingly possible to prevent the oxidation of SA-PC just aseffectively with the reduced dithiol compounds according to theinvention (Examples 49 and 50) as with the corresponding oxidized dithiocompounds (Examples 51 and 52 without free SH groups).

Method V Inhibiting Effect on Fatty Acid Oxidation in Rat Mitochondria

(Malonaldehyde determination by the thiobarbiturate method according toOttolenghi, Arch. Blochem. Biophys. 79 (1959) pp. 355 et seq.). Thedetermination was carried out spectrophotometrically in mitochondrialhomogenates from rats. The inhibition of fatty acid oxidation by thepreparations according to the invention was virtually complete.

Method VI Inhibition of Lipid Oxidation in Liposomal Biomembranes

An aqueous solution of liposomes (Nattermann, Cologne/Germany) wasdiluted with double-distilled water until the absorption measured at 234run against air in a spectrophotometer (PMQ II from Zeiss,Oberkochen/Germany) was between 0.25 and 0.35 (corresponds to about 0.1mg of liposomes/ml). 50 mcmol/l of cumene hydroperoxide and 12 mcmol ofhematin were then added to this liposome suspension (total volume 1 ml)and the increase in the absorption at 234 run was monitored periodicallyas a measure of the rate of liposome oxidation.

It was possible to suppress the oxidation of the liposomes by additionof the antioxidants according to the invention. The following tableshows the mean increase in ΔE₂₃₄ /min in batches with and withoutantioxidant after 25 min at 25° C.

                  TABLE                                                           ______________________________________                                                           ΔE.sub.234 /min                                      ______________________________________                                        without addition of antioxidant                                                                    0.035                                                    with addition of 100 nmol/l of                                                                     0.005                                                    antioxidant according to the                                                  invention                                                                     to                   0.015                                                    ______________________________________                                    

Even better results are obtained if the lipophilic antioxidants areadditionally incorporated during the preparation of the liposomes ascomponents thereof.

Method VII

Inhibition of LDL oxidation according E1-Saadani et al., Journal ofLipid Research 30 (1989) page 627

Analogously to method VI, the lipophilic antioxidants also protect"Low-Density Lipoprotein" (Sigma, St. Louis, USA) from oxidation.

Method VIII Laser-Induced Thrombosis in Rats in Vivo

The experimental procedure was carried out in every detail as describedin U.S. Pat. No. 4,694,024. Laser induction took place 60 min after oraladministration of the antioxidants. After oral administration of theantioxidants according to the invention (30 mg/kg), a significantlyhigher number of laser pulses was necessary than in the comparisonexperiments, i.e. the thrombosis-inhibiting power of resistance of theanimals was higher after administration of the antioxidants according tothe invention.

    ______________________________________                                                         Reduction of thrombus                                                         formation                                                    ______________________________________                                        Compound acc. to Example 13                                                                      17%                                                        Compound acc. to Example 52                                                                      14%                                                        Compound acc. to Example 49                                                                      20%                                                        Compound acc. to Example 47                                                                      15%                                                        Compound acc. to Example 3                                                                       11%                                                        Compound acc. to Example 2                                                                       14%                                                        Compound acc. to Example 1                                                                       16%                                                        Compound acc. to Example 36                                                                      17%                                                        Compound acc. to Example 33                                                                      13%                                                        (4,4,-(Isopropylidene-                                                                            6%                                                        dithio)bis[2,6-di-tert.-                                                      butylphenol]                                                                  Vitamin E           5%                                                        ______________________________________                                    

Method IX Photochemically-Induced Thrombus Formation in Rats in Vivo

The measurements were carried out on mesenterial arterioles. To this end0.3 ml of a solution of fluorescein isothiocyanate-dextran 70(FITC-Dextran, Sigma, Seidenhofen, FRG) was injected, and the arterioleswere then irradiated with light (490 run) in the observation field. Thethrombi formed as a result were quantified by vital microscopy, asdescribed under Method VIII. Using antioxidants according to theinvention, it was possible to inhibit the thrombus formation one hourafter oral administration of 50 mg/kg of rat body weight by up to 20%.

Method X

Arachidonic acid-induced platelet aggregation according to Ruppert andWeithmann, Life Sciences 31 (1982) 2037 et seq.

The antithrombotic effect of the substances according to the inventionhas not come about as a result of an inhibition of platelet aggregation,since no significant inhibitory action was to be detected up to 10mcmol/l of the substances according to the invention. Thus, an increasedproneness to bleeding of patients who are treated with these substancesis not expected.

Method XI

Effect of the compounds according to the invention on long-termadministration in the hyperlipidemic infarct-sensitive rat:

Male infarct-sensitive rats about 200 g in weight (Mollegaard, EJby,Derunark) were treated orally once daily with 1 ml/100 g of body weightof a standard diet (100 g of cholic acid, 100 g of cholesterol, 30 g ofpropylthiouracil to 1 l of sesame oil). While no test substance wasadministered to the control group I (cf. the following Table), thestandard diet in the pharmaceutical experiments II-IV additionallycontained 50 mg/kg of body weight of the test substances indicated inthe table below. After 9 days, the rats were examined, as describedabove, in the laser-induced thrombosis test, and the total cholesterolcontent of the serum was determined. It can be seen from the followingtable that the proneness to thrombosis of the hyperlipidemicinfarct-sensitive rats in comparison to healthy rats (<100 mg ofcholesterol/dl) can be treated with the substances according to theinvention surprisingly more successfully than with vitamin E. Moreover,the substances according to the invention exerted an advantageoushypolipidemic effect.

    ______________________________________                                                                         Reduction in                                                        Total     proneness to                                             Number of  cholesterol                                                                             thrombosis                                   Group       animals n =                                                                              mg/dl     vs. control (%)                              ______________________________________                                        I    Control    5          286     --                                         II   Vitamin E  6          278     26                                         III  Compound   4          270     50                                              according to                                                                  Example 2                                                                IV   Compound   5          259     34                                              according to                                                                  Example 49                                                               ______________________________________                                    

We claim:
 1. A compound of the formula I

    (A).sub.a (L)(X).sub.a,                                    (I)

in which a and a' independently of one another are 1 or 2, A is anantioxidative component A₁, a chroman partial structure of vitamin E, ofthe following formula ##STR112## in which Q represents a free valency; Lis a bridging member composed of one or more of the building blocks ofthe following formulas ##STR113## in which R¹⁰, R¹¹ and R¹² are H, alower alkyl radical or Q, or in which R¹¹ is --CO_(a) R¹⁰ wherein a is 1or 2, and 2 radicals selected from --O--, --S-- and --NR¹⁰ -- areseparated from one another by at least 1 carbon or phosphorus atom; andX is a lipophilic component X₁, a cholane derivative radical, of thefollowing formula ##STR114## in which R¹³ is sec. C₄ H₉, R¹¹ is the sameas defined in L or Q, E is O, S, NR¹⁰ as defined in L, α, β-OH, H or α,β-Q, H and a double bond can be present in the 4,5- or 5,6- or7,8-position.
 2. A method of treating a host affected by thrombosiswhich comprises treating said host with an effective amount of acompound of formula I of claim
 1. 3. A pharmaceutial composition fortreating thrombosis, comprising an effective amount of a compound of theformula I as claimed in claim 1, together with a pharmacologicallytolerable excipient.